The principal objective for this SBIR Phase II Competitive Renewal project is to demonstrate clinical relevance of a unique Adaptive Optics Scanning Laser Ophthalmoscope (AOSLO) that the project team designed and built in Phase I and Phase II work. It features closed-loop AO control that automatically compensates for aberrations of the eye, yielding nearly diffraction-limited confocal retinal images. This is particularly useful in retinal imaging, since the difference in resolvable feature size with AO (~2m) and without AO (~10m) corresponds to a range that includes the size of many of the retina's most important features: cone photoreceptors, nerve fiber cells, erythrocytes, leukocytes, capillaries, and retinal pigment epithelial cells. As a result, the AOSLO should lead to a better understanding of retinal function and disease. The prototype AOSLO incorporates an optical doubler and custom-developed long-stroke deformable mirror for compensating higher order aberrations. Those unique components allow aberration- compensated imaging suitable for 90% of clinical subjects without the use of added trial lenses. In Phase II work, the AOSLO was demonstrated to achieve exceptional retinal image resolution and operational characteristics that make it well suited for clinical use. It uses long wavelength and low intensit source illumination, so that many subjects can be imaged without pupil dilation. It also includes a beam steering system that allows a clinician to translate the imaged field across the retina without requiring continual subject refixations. Innovative imaging techniques that will be explored in the clinical settings using this AOSLO platform technology include individual blood cell tracking, hemodynamic imaging, and montage mapping of photoreceptors. The project will include development of clinically inspired enhancements in imaging, ergonomics, and software control of the prototype AOSLO. BMC will collaborate with a clinical site in an evaluation of the clinical usefulness of the AOSLO. Observational pilot studies will be conducted at Beetham Eye Institute (BEI) of the Joslin Diabetes Center Clinical aims for the BEI study will be to evaluate the capability of AOSLO retinal images to serve as a clinically useful surrogates for visual acuity in eyes with center-involved diabetic macular edema, and to evaluate correlations between quantified AOSLO image metrics and the state of retinal disease in diabetic retinopathy.